ผู้เขียน หัวข้อ: Dapagliflozin, advanced chronic kidney disease, and mortality: new insights from  (อ่าน 28 ครั้ง)

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Dapagliflozin, advanced chronic kidney disease, and mortality: new insights from
« เมื่อ: พฤษภาคม 09, 2021, 22:35:19 »
แทงบอลสเต็ป 3
Effect of sodium–glucose co-transporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) or heart failure with reduced ejection fraction (HFrEF). CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HF, heart failure. *Data from DAPA-CKD5,6. #Data from a meta-analysis from DAPA-HF and EMPEROR-Reduced.8

In the general population, both decreasing estimated glomerular filtration rate (eGFR) and increasing albuminuria are well-established predictors of overall mortality. The presence of diabetes mellitus further potentiates this relationship.1 In chronic kidney disease (CKD) stages 4–5, ∼50% of patients suffer from cardiovascular disease, and cardiovascular mortality accounts for ∼40–50% of all deaths in patients with CKD stage 4 as well as patients with end-stage kidney disease (ESKD), compared with 26% in controls with normal kidney function.2 In terms of cardiovascular disease and mortality, the relative importance of heart failure, valvular and sudden cardiac death, but not ischaemic heart disease, increases as CKD progresses.2 In a multitude of studies in subjects with advanced CKD, correction for classical cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidaemia, did not neutralize the impact of CKD on cardiovascular risk,3 supporting the conclusions of a large meta-analysis that diabetes and kidney disease serve as independent predictors of clinical outcomes.1 These observations underline the importance of non-traditional, CKD-specific cardiovascular risk factors and may explain at least in part why traditional strategies to improve cardiovascular outcome have largely failed in the context of CKD.4 Also, this emphasizes the need not only to identify pathological mechanisms adversely affecting the cardiovascular system in CKD but also to develop novel therapeutic strategies. However, in most outcome trials conducted in the different fields of cardiology, patients with advanced CKD have been excluded, resulting in an unfortunate and serious lack of evidence-based recommendations for this particular high-risk group.

In this issue of the European Heart Journal, Heerspink et al.5 present a pre-specified analysis from the randomized, placebo-controlled DAPA-CKD (Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease) trial,6 in which they studied the effects of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on morbidity and mortality in patients with CKD. The trial had been performed in a population of diabetic but also non-diabetic CKD patients with a mean eGFR of 43 mL/min/1.73 m2. In DAPA-CKD, dapagliflozin as compared with placebo led to a significant reduction in the primary composite endpoint of a sustained ≥50% eGFR decline, ESKD, renal or cardiovascular death, as well as hospitalization for heart failure. In the present analysis, the authors now show that among the 247 deaths in DAPA-CKD (i.e. 5.7% of the overall population), 37% were due to cardiovascular causes, 41% due to non-cardiovascular causes, and 22% were of undetermined cause. Over a median follow-up of 2.4 years, dapagliflozin led to a highly significant 31% risk reduction of all-cause mortality with a significant reduction in patients both with and without diabetes; moreover, the results were consistent across all other pre-specified subgroups. Interestingly, the effect on all-cause mortality was largely driven by a significant 46% relative risk reduction of non-cardiovascular death, while the effect on cardiovascular death was not significant. Albeit only seen in a small number of patients and only described as a post-hoc analysis, the reduction in non-cardiovascular deaths by dapagliflozin was mainly driven by a reduction in deaths due to infections and malignancies.

The authors should be congratulated for conducting this landmark trial in the underinvestigated population of high-risk patients with advanced CKD and for providing these pre-specified analyses to the scientific community. The results of this mortality analysis are important for several reasons. First, our current knowledge of the causes of death in patients with CKD is mainly based on observational studies with the inherent limitations of medical databases and registers, such as lack of adjudication and potential misclassification. In the DAPA-CKD trial, mortality data were adjudicated by an independent events committee and they are derived from a very well characterized study population. The DAPA-CKD data thus extend our knowledge on the causes of death in patients with advanced CKD in that non-cardiovascular deaths occurred at a similar frequency to cardiovascular deaths (see above). Among the non-cardiovascular deaths, patients mainly died because of infection (19%) and malignancies (11%), while cardiovascular deaths mostly resulted from sudden cardiac death (21%) followed by 5.5% due to heart failure and only in 4.5% of the cases from acute myocardial infarction. This is remarkably similar to observations in diabetic patients on dialysis, for example in the 4D study7 where sudden cardiac death was the most prominent cause of cardiovascular mortality. The important insight from DAPA-CKD is, thus, that in CKD the shift towards more and more sudden cardiac deaths occurs long before the ESKD state has been reached